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Effect of flubendazole on glioblastoma multiforme in vitro and in vivo.
Šteigerová, Monika ; Boušová, Iva (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Monika Šteigerová Supervisor: doc. PharmDr. Iva Boušová, Ph.D., RNDr. Veronika Skarková, Ph.D. Title of diploma thesis: Effect of flubendazole on glioblastoma multiforme in vitro and in vivo. Glioblastoma multiforme (GBM) is the most common malignant glioma of the central nervous system. Despite systematic complex treatment, the median survival of this malignity is 14 months. Anthelmintic and potential anticancer drug flubendazole (FLU) is recently studied for its antiproliferative effect in various tumor cells (1). The aim of our project was to investigate the effect of FLU on GBM cell lines U118MG (stabilized cell line) and GBM69 (primary cell line) in vitro, tumor growth in vivo, and its effect on mRNA and protein levels of selected markers of epithelial-mesenchymal transition and drug resistance. First-line chemotherapeutic temozolomide (TMZ) was used as a positive control. Both tested cell lines were more sensitive to FLU treatment in comparison with TMZ. Indeed, FLU caused more apparent morphological changes than TMZ in these cells. FLU significantly influenced mRNA and protein levels of E-cadherin, N-cadherin, vimentin, as well as resistance markers MGMT or MRP-1. In addition, subcutaneous...
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Cytotoxicity of semisynthetic derivatives of prenylflavonoids in breast carcinoma cells
Hupák, Martin ; Boušová, Iva (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Martin Hupák Supervisor: doc. PharmDr. Iva Boušová, Ph.D. Advisor: PharmDr. Martin Ambrož, Ph.D. Title of diploma thesis: Cytotoxicity of semisynthetic derivatives of prenylflavonoids in breast carcinoma cells Cancer is a cause of a significant portion of death in the human population. In the Czech Republic, breast cancer is the most common type of cancer in women. Pharmacological treatment of cancer is often accompanied by resistance development, so new treatment options are still searched for and natural compounds are one of the sources of new structures. Prenylflavonoids present in common hop (Humulus lupulus, Cannabaceae), for example, xanthohumol, isoxanthohumol, 8-prenylnaringenin, 6- prenylnaringenin, possess a wide spectrum of biological effects. One of them is an anti- cancer effect. This diploma thesis dealt with the determination of the cytotoxic potential of semisynthetic prenylated derivatives of flavonoid naringenin in breast carcinoma cell line MCF-7. Methods used included the determination of cytotoxicity using neutral red uptake assay, analysis of apoptosis and necrosis using flow cytometry, determination of mitochondrial membrane potential using JC-1 probe, and analysis of...
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Photochemical internalization of saporine by phthalocyanine photosensitisers
Vlková, Kateřina ; Macháček, Miloslav (advisor) ; Kozlíková, Magdaléna (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Student: Bc. Kateřina Vlková Supervisor: RNDr. Miloslav Macháček, Ph.D. Consultant: Mgr. Monika Rohlíčková Title of the diploma thesis: Photochemical internalization of saporine by phthalocyanine photosensitisers The application of therapeutic macromolecules is often affected by limited cellular uptake and lysosomal degradation, thus failing to reach their intracellular targets. Their cellular uptake can be increased through photochemical internalization. Photochemical internalization uses photosensitive agents that localize in the membranes of endosomes and induce drug release upon exposure to light. This diploma thesis is focused on the evaluation of the effect of saporin in the combination with non-symmetrical photosensitizers on HeLa cell line using photochemical internalization. Effect of various concentrations of these compounds on the viability of tumour cells was evaluated. Two approaches to deliver the energy from light were compared as well: before and after the administration of saporin (i.e., "light-before" and "light-after" approach). From obtained data, it is evident that saporin (administered alone) does not significantly reduce the viability of HeLa cells, even though it was applied in a...
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Modulation of anti-inflammatory response in microglial cell line SIM-A9
Hapalová, Jitka ; Macháček, Miloslav (advisor) ; Kobrlová, Tereza (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Jitka Tumpachová Supervisor: RNDr. Miloslav Macháček, Ph.D. Consultant: pplk. doc. MUDr. Jaroslav Pejchal, Ph.D. et Ph.D. Title of diploma thesis: Modulation of anti-inflammatory response in microglial cell line SIM-A9 In the theoretical section, the thesis is focused on the characteristics, significance, and contribution of neuroinflammation in the origin and development of neurodegenerative diseases. The possibilities of their current treatment are discussed. The experimental part is devoted to evaluating the cytotoxicity and anti-inflammatory response of newly synthesized derivatives of naphthoquinones (K1502, K1503 and K1504) and chromones (5-EM-13, 5-EM-26 and 5-EM-36). Cytotoxicity was measured in the mouse microglial line SIM-A9. In addition, the neuroblastoma line SH-SY5Y was used comparatively in this part. The half-maximal inhibitory concentration (IC50) and maximum tolerated concentration (MTC) were determined on both cell lines using MTT colorimetric methods. The safety of MTC was subsequently verified by microcapillary flow cytometry in the SIM-A9 cells after lipopolysaccharide (LPS) or interferon-γ (IFN-γ) stimulation. The anti-inflammatory effects of the studied substances were...
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Organ distribution of anionic phthalocyanine photosensitizers in a mouse tumor model.
Kožená, Iva ; Macháček, Miloslav (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Author: Bc. Iva Kožená Supervisor: RNDr. Miloslav Macháček, Ph.D. Consultant: PharmDr. Jan Kollár, Ph.D. Title of diploma thesis: Organ distribution of anionic phthalocyanine photosensitizers in a mouse tumor model Cancer treatment currently consists mainly of chemotherapy, radiotherapy, and surgery. As these treatments possess certain side effects, other ways of treating cancer are being explored. One of these modern approaches, which is the subject of intensive research around the world, is a non-invasive and minimally toxic method called photodynamic therapy (PDT). The PDT is based on the application of a light-sensitive substance called a photosensitiser (PS), which accumulates selectively in the tumour and, after exposure to a light of a suitable wavelength, a photochemical reaction occurs which leads to the production of reactive oxygen species. The result of this reaction is an oxidative stress in the tumour tissue together with cellular damage with subsequent cell death accompanied with vascular damage, and even stimulation of the immune response. Due to their advantageous properties, the phthalocyanines (Pcs) are very promising PSs. They are usually prepared in the form of complexes with centrally...
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Cytotoxicity of semisynthetic derivatives of prenylflavonoids in breast carcinoma cells
Hupák, Martin ; Boušová, Iva (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Martin Hupák Supervisor: doc. PharmDr. Iva Boušová, Ph.D. Advisor: PharmDr. Martin Ambrož, Ph.D. Title of diploma thesis: Cytotoxicity of semisynthetic derivatives of prenylflavonoids in breast carcinoma cells Cancer is a cause of a significant portion of death in the human population. In the Czech Republic, breast cancer is the most common type of cancer in women. Pharmacological treatment of cancer is often accompanied by resistance development, so new treatment options are still searched for and natural compounds are one of the sources of new structures. Prenylflavonoids present in common hop (Humulus lupulus, Cannabaceae), for example, xanthohumol, isoxanthohumol, 8-prenylnaringenin, 6- prenylnaringenin, possess a wide spectrum of biological effects. One of them is an anti- cancer effect. This diploma thesis dealt with the determination of the cytotoxic potential of semisynthetic prenylated derivatives of flavonoid naringenin in breast carcinoma cell line MCF-7. Methods used included the determination of cytotoxicity using neutral red uptake assay, analysis of apoptosis and necrosis using flow cytometry, determination of mitochondrial membrane potential using JC-1 probe, and analysis of...
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Effect of flubendazole on glioblastoma multiforme in vitro and in vivo.
Šteigerová, Monika ; Boušová, Iva (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Monika Šteigerová Supervisor: doc. PharmDr. Iva Boušová, Ph.D., RNDr. Veronika Skarková, Ph.D. Title of diploma thesis: Effect of flubendazole on glioblastoma multiforme in vitro and in vivo. Glioblastoma multiforme (GBM) is the most common malignant glioma of the central nervous system. Despite systematic complex treatment, the median survival of this malignity is 14 months. Anthelmintic and potential anticancer drug flubendazole (FLU) is recently studied for its antiproliferative effect in various tumor cells (1). The aim of our project was to investigate the effect of FLU on GBM cell lines U118MG (stabilized cell line) and GBM69 (primary cell line) in vitro, tumor growth in vivo, and its effect on mRNA and protein levels of selected markers of epithelial-mesenchymal transition and drug resistance. First-line chemotherapeutic temozolomide (TMZ) was used as a positive control. Both tested cell lines were more sensitive to FLU treatment in comparison with TMZ. Indeed, FLU caused more apparent morphological changes than TMZ in these cells. FLU significantly influenced mRNA and protein levels of E-cadherin, N-cadherin, vimentin, as well as resistance markers MGMT or MRP-1. In addition, subcutaneous...
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Study of the novel phtalocyanines for the vascular-targeted photodynamic therapy of tumors
Brázdová, Petra ; Macháček, Miloslav (advisor) ; Šimůnek, Tomáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Petra Brázdová Supervisor: Mgr. Miloslav Macháček Title of diploma thesis: Study of the novel phthalocyanines for the vascular-targeted photodynamic therapy of tumors Cancer is one of the leading causes of death in developed countries, therefore a big effort is devoted on research of novel anticancer drugs. Photodynamic therapy (PDT) is currently a well-established method in this area, but targeting its effect on tumor vasculature has not been considered until recently. In comparison with PDT, vascular-targeted photodynamic therapy (VTP) takes the advantage of a much shorter interval between administration of the photosensitizer (PS) and irradiation (drug-light interval) and thus turning the effect of cytotoxic agents to tumor vasculature. It is intended to disrupt the oxygen and nutrients supply to malignant cells and thus cause their damage and death. Aim of this work is to evaluate the efficacy of newly synthesized PSs from the group of phthalocyanines and azaphthalocyanines using the VTP protocol under in vitro conditions. The PSs used in this study have been investigated recently with classical PDT protocol, in which they have demonstrated very promising activity against tumor cells...
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Evaluation of photodynamic activity of tetrapyridoporphyrazine derivatives for treatment of tumorous diseases.
Půlkrábková, Martina ; Macháček, Miloslav (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Martina Půlkrábková Supervisor: Mgr. Miloslav Macháček, Ph.D. Title of diploma thesis: Evaluation of photodynamic activity of tetrapyridoporphyrazine derivatives for treatment of tumorous diseases. Cancerous diseases are one of the most common causes of death, especially in industrialized countries. Their more effective treatment requires development of new potential anti-tumor agents and therapeutic methods. Photodynamic therapy (PDT) is a clinically approved method for the treatment of both tumorous and some other diseases. Its main advantages are non-invasiveness and potential for high selectivity to target cells, which distinguishes it from current conventional anticancer treatments (chemotherapy, radiotherapy). The effect of PDT is based on a combination of three effective components - molecular oxygen, light and photosensitiser (PS). These substances are inherently non-toxic, but they can form reactive oxygen species (ROS) if combined. Then, ROS significantly damages cellular structures in target cells, which can result in cell death. PS is a substance capable of absorbing light of suitable wavelength and transferring the received energy to surrounding molecules, to molecular oxygen in...
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